Progress in the treatment of chronic lymphocytic leukemia: results of the German CLL8 trial

Until now, no approach that is able to improve overall survival of chronic lymphocytic leukemia (CLL) patients has been available. In the German CLL Study Group (GCLLSG) CLL8 trial, treatment-naive, physically fit patients (aged 30–81 years) with CD20⁺ CLL were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m² per day) and cyclophosphamide (250 mg/m² per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m² on day 0 of first course and 500 mg/m² on day 1 of second to sixth courses). The two groups were well balanced with respect to baseline characteristics. The study was stopped at the preplanned interim analysis owing to an advantage in the median progression-free survival in the chemoimmunotherapy arm (51.8 vs 32.8 months; hazard ratio: 0.56; 95% CI: 0.46–0.69; p < 0.0001). Furthermore, at 3 years after randomization, 87% of patients in the chemoimmunotherapy group were alive compared with 83% in the chemotherapy group (hazard ratio: 0.67; 95% CI: 0.48–0.92; p = 0.01). In terms of toxicity, chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (p < 0.0001). There were eight (2%) treatment related-deaths in the chemoimmunotherapy arm compared with ten (3%) in the chemotherapy arm. The CLL8 trial has demonstrated that an association of rituximab, fludarabine and cyclophosphamide is effective in prolonging progression-free survival and overall survival of patients with symptomatic CLL, therefore establishing the new standard of treatment for physically fit patients.     

Choosing first-line therapy for chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) exhibits a highly variable natural history, but the addition of genomic risk stratification to traditional clinical staging systems has begun to explain the heterogeneous clinical course. Overall response to treatment has significantly improved over the past three decades and for the first time, a survival benefit has been demonstrated with the use of monoclonal antibodies in combination with cytotoxic chemotherapy. Newer therapeutic strategies have abrogated the adverse prognosis associated with some higher risk features, but other genetic subgroups remain at high risk for rapid disease progression and early mortality. Patients at advanced age or with significant comorbidity constitute a large proportion of the CLL population and present unique clinical challenges. This article will discuss the evolution of contemporary therapeutic approaches to the initial treatment of CLL, and highlight the ways in which risk-adapted therapeutic strategies are improving clinical outcomes.     

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.     

Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up.

BACKGROUND: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic-polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer. PATIENTS AND METHODS: From 1984 to 1989, patients who had D(2-3) curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m2 adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections. RESULTS: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T2-T4a), and lymph node status (N0-N2). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T3/T4a, N2, or stage III. Treatments were generally well tolerated in both arms. CONCLUSIONS: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.     

Therapeutic concepts in mantle cell lymphoma

Mantle cell lymphoma has been considered an incurable disease with current chemotherapy regimens. Recent intense chemoimmunotherapy induction regimens with or without consolidation with autologous stem cell transplantation procedures are showing a potential for cure in a sizable fraction of patients. Similarly, in the salvage setting, preliminary experience with non‐myeloablative allogeneic transplant may cure some patients even after multiple therapeutic failures. However, the recent knowledge of the three basic biologic derangements that are integrated in the disease may change the therapeutic approach of the disease in the near future. In fact, new drugs that target more specifically the major molecular alterations of the disease are being progressively incorporated into the therapeutic armamentarium of the disease. In the near future, more individualized approaches that will take into account not only risk factors present at diagnosis but also biomarkers representative of the molecular alterations present in the disease are foreseen. In this review, we are going to discuss the current therapeutic approaches and the main new drugs that target more specifically the major molecular pathways alterations of the disease.     

Chemoimmunotherapy with or without oophorectomy in premenopausal patients with advanced breast cancer.

Ninety-eight premenopausal patients with stage IV breast cancer were treated with chemoimmunotherapy alone, or with combination oophorectomy-chemoimmunotherapy either simultaneously (chemoimmunotherapy within four weeks of oophorectomy) or sequentially (delayed chemoimmunotherapy until evidence of progressive disease or no response to oophorectomy). The chemoimmunotherapy consisted of a three-drug combination of Adriamycin, cyclophosphamide, and 5-fluorouracil or Ftorafur; immunotherapy consisted of either oral levamisole, BCG by scarification, or a combination of both. Forty patients underwent simultaneous oophorectomy-chemoimmunotherapy, with a response rate of 85% and a median duration of response of 25 months. Response rate of 69% and a median duration of response of 16.6 months was observed with the 29 patients who received sequential oophorectomy-chemoimmunotherapy. Another 29 patients were treated with chemoimmunotherapy alone and achieved a response rate of 87% and a median duration of response of 11.8 months. Though there were no significant differences in the response rate, patients treated with chemoimmunotherapy alone had a significantly shorter median duration of response (P less than 0.05). This would suggest that oophorectomy in combination with chemoimmunotherapy is the most favorable treatment modality for premenopausal patients with advanced metastatic breast cancer.     

Selection of gastrectomy for adenocarcinomas arising in the gastric fundus

A retrospective study involving 174 patients with adenocarcinoma of the gastric fundus treated with proximal subtotal (PS), extended proximal subtotal (EPS), total (T), and extended total (ET) gastrectomy showed that 1)there were no statistically significant differences in operative mortality between the four gastrectomy types; 2)ET was associated with a significantly lower incidence of local recurrence than T (P less than 0.05) and PS (P less than 0.001); 3)ET resulted in a significantly higher survival rate than PS or T (P less than 0.01) when the three procedures were applied in patients who had TNM stage I and II tumors; 4)patients with stage III and IV tumors did poorly regardless of gastrectomy type. The study implies that intraoperative tumor staging might identify stage I and II patients who benefit the most from radical surgery and those with stage III and IV tumors who should receive palliative surgery.